Angiotensin ii antagonist 1,3-imidazoles and use thereas

ABSTRACT

This invention provides novel phenyl and heterocyclic derivatives, their pharmaceutical formulations and their use for antagonizing angiotensin II receptors in mammals.

BACKGROUND OF THE INVENTION

The hormone angiotensin II is recognized as the most potent vasopressoragent that produces hypertension in mammals. The action of the enzymerenin on the plasma protein substrate angiotensinogen results in theproduction of an inactive decapeptide, angiotensin I, which, uponconversion by the nonselective angiotension converting enzyme (ACE)provides angiotensin II, the active hormone. See, e.g., Regoli et al.,Pharm. Rev., 26, 69 (1974). Angiotensin II causes vasoconstriction andstimulates aldosterone secretion (from the adrenal gland) which resultsin a rise of both blood volume and pressure. Angiotension II also canact on other organs such as the brain (Fitzsimmons, Rev. Physiol.Biochem. Pharmacol., 87, 117, (1980)), and a variety of glandulartissues including the kidney, liver and ovaries. Angiotensin II may alsohave a role in regulating the rate of cell growth and differentiation.See, e.g., Naftilan et al., J. Clin. Invest., 83, 1419 (1989), andJackson et al., Nature, 335, 437 (1988).

Some antihypertensive agents act as inhibitors of ACE thus blocking theformation of angiotensin II and its resulting increase of bloodpressure. More recently, both peptide and non-peptide antagonists ofangiotensin II have been disclosed--see, e.g., EPO Patent ApplicationPublication 253310 and references contained therein, and Chiu et al., J.Pharmacol. Exp. Ther., 250, 867 (1989).

The present invention provides novel, potent, and effective compoundsthat antagonize angiotensin II at receptor sites in the body and aretherefore useful as antihypertensive agents and for the treatment ofcongestive heart failure. (Douglas, W. W., in The Pharmacological Basisof Therapeutics, 7th Edition, Eds. A. G. Gilman, L. S. Goodman, T. W.Roll and F. Murod, MacMillan Publishing Co., New York, 1985) p. 652.

SUMMARY OF THE INVENTION

This invention provides compounds of Formula I ##STR1## andpharmaceutically acceptable salts thereof ##STR2## each of A₁, A₂, andA₃ is independently N or CH; X is --CO--, --CONH--, --NHCO--, --CH₂CONH--, --O--, --NH--, --CH₂ -- or a bond;

each R₁ is independently --(CH₂)_(n) R₃ ;

R₂ is C₄ -C₇ straight chain alkyl;

each R₃ is independently --OH, --COOH, or 5-tetrazolyl;

each n is independently 0, 1, 2, 3 or 4;

R₄ is H, OH, halo, nitro, methyl, amino, acetamido, ormethanesulfonamido;

Q is a bond or --O--; and

W is H, methyl, ethyl, or hydroxy.

This invention also provides a method for treating hypertension whichcomprises administering to a mammal in need of such treatment anantihypertensive amount of a compound of Formula I.

Also provided are pharmaceutical formulations comprising a compound ofFormula I together with one or more pharmaceutically acceptableexcipients, carriers, or diluents therefor.

One further aspect of this invention is compounds which areintermediates for preparing the compounds of Formula I. These compoundsare represented by Formula I'. ##STR3## each of A₁, A₂, and A₃ isindependently N or CH; X is --CO--, --CONH--, --NHCO--, --CH₂ CONH--,--O--, --NH--, --CH₂ -- or a bond;

each R₁ ' is independently --(CH₂)_(n) R₃ ';

R₂ is C₄ -C₇ straight chain alkyl;

each R₃ ' is independently --OH, --COOH, 5-tetrazolyl, --COO(C₁ -C₄alkyl), or --CN;

each n is independently 0, 1, 2, 3, or 4;

R₄ is H, OH, halo, nitro, methyl, amino, acetamido, ormethanesulfonamido;

Q is a bond or --O--; and

W is H, methyl, ethyl, or hydroxy;

provided at least one R₃ ' is --COO(C₁ -C₄ alkyl) or --CN.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENT

Preferred compounds of this invention are those of Formula I wherein Gis either phenylene or imidazolenyl, Ar is R₃ -substituted phenyloptionally substituted with hydroxy, X is --CONH--, n is 0, and R₂ isn-hexyl. Particularly preferred compounds are those of Formula Ia:##STR4## wherein R₄ ' is hydrogen or hydroxy. Most preferred compoundsare those wherein n is 0 and each R₃ is independently --COOH or5-tetrazolyl.

As used in this document, the term "C₁ -C₄ alkyl" includes methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.The term "C₄ -C₇ straight chain alkyl" includes n-butyl, n-pentyl,n-hexyl, and n-heptyl. The term "halo" includes fluoro, chloro, bromo,and iodo.

In the definition of Formulas I and I', the G heterocyclic functionalityis attached to X at the carbon atom between atoms A₁ and A₂. Thus, the--CHR₁ R₂ substituent is attached to the nitrogen atom.

Similarly, while both the "normal" and "reverse" amides of linking groupX are contemplated, only those acetamido functionalities wherein Ar-X-Gis Ar--CH₂ CONH--G are contemplated.

By virtue of their acidic carboxylic acid or tetrazole moieties, thecompounds of Formula I include the pharmaceutically acceptable baseaddition salts thereof. Such salts include those derived from inorganicbases, such as ammonium and alkali and alkaline earth metal hydroxides,carbonates, bicarbonates, and the like, as well as salts derived frombasic organic amines, such as aliphatic and aromatic amines, aliphaticdiamines, hydroxy alkylamines, and the like. Such bases useful inpreparing the salts of this invention thus include ammonium hydroxide,potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine,diethylamine, ethyl nediamine, cyclohexylamine, ethanolamine, and thelike. The potassium and sodium salt forms are particularly preferred.

The compounds of Formula I where G is a heterocycle can also exist aspharmaceutically acceptable acid addition salts. Acids commonly employedto form such salts include inorganic acids such as hydrochloric,hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well asorganic acids such as paratoluenesulfonic, methanesulfonic, oxalic,para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and aceticacid, and related inorganic and organic acids. Such pharmaceuticallyacceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite,bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, decanoate, caprylate, acrylate, formate, isobutyrate,caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate,phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,hippurate, β-hydroxybutyrate, glycollate, maleate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like salts. The hydrochloridesalt form is particularly preferred.

The pharmaceutically acceptable salts of compounds of Formula I can alsoexist as various solvates, such as with water, methanol, ethanol,dimethylformamide, and the like. Mixtures of such solvates can also beprepared. The source of such solvate can be from the solvent ofcrystallization, inherent in the solvent of preparation orcrystallization, or adventitious to such solvent.

It is recognized that various stereoisomeric forms of the compounds ofFormula I and I' exist, for example, the chiral carbon atom to which G,R₁ or R₁ ', and R₂ are attached. This invention is not limited to anyparticular stereoisomer but includes all possible individual isomers andmixtures thereof.

The compounds of Formula I are prepared by standard methods fromintermediates I'. Those compounds of Formula I' wherein one or more ofR₃ ' is cyano can be converted either to the 5-tetrazolyl final product(R₃ is 5-tetrazolyl) or the carboxylic acid final products (or the saltsthereof) by methods known in the art. Thus, the cyano intermediates aretreated with an alkali metal azide such as sodium azide, ammoniumchloride or triethylamine hydrochloride, and (optionally) lithiumchloride in a non-reactive high boiling solvent such asN,N-dimethylformamide (DMF), preferably at temperature from about60°-125° C. Alternatively, tri-(n-butyl)tin azide ortetramethylguanadinium azide, in a solvent such as tetrahydrofuran,dimethoxyethane, diethoxyethane, or the like, may be used in place ofthe alkali metal azide, ammonium chloride, lithium chloride, and DMF.

The carboxylic acids of Formula I can be prepared by hydrolysis ofeither the cyano or ester intermediates of Formula I'. The hydrolysisgenerally involves the heating of the cyano derivative in aqueousalcohol in the presence of a base such a sodium or potassium hydroxide.When the ester intermediate is employed, it is treated with aqueoussodium or potassium hydroxide solution optionally in the presence of analcohol preferrably at a temperature from approximately 50° C. up to thereflux temperature of the mixture. The free acid final product can beisolated by acidifying (for example, with 5N hydrochloric) the cooledreaction mixture. The salts of the carboxylic acid and tetrazole finalproducts are made by reacting the free acid or tetrazole with theappropriate base by standard procedures.

The desired products from the above reactions can be isolated byconventional means, and preferably by chromatography. Columnchromatography is a preferred method and high pressure columnchromatography over silica gel offers a most efficient way of purifyingthe final products. Alternatively, crystallization of the acid,tetrazole, or salts may be employed to purify the desired final product.

One process for preparing the heterocyclic intermediates of Formula I'involves the alkylation of intermediate II with an alkylating reagentIII to prepare intermediate IV as summarized by Scheme 1 ##STR5## whereAr', X, R₁ ' and R₂ are the same as previously defined, G' is ##STR6##and L is a good leaving group such as chloro, bromo, iodo, mesyl, tosyl,and the like. This reaction usually involves approximately equimolaramounts of the two reagents, although other ratios, especially thosewherein the alkylating reagent is in excess, are operative. The reactionis best carried out in a polar aprotic solvent employing an alkali metalsalt or other such alkylation conditions as are appreciated in the art.When the leaving group is bromo or chloro, a catalytic amount of aniodide salt, such as potassium iodide, may be added to speed thereaction. Preferred reaction conditions include the following: lithiumbromide and dimethylformamide, potassium fluoride on alumina, sodiumbicarbonate in dimethylformamide, sodium hydride in dimethylformamide,potassium carbonate, potassium iodide, and either methylethyl ketone oracetone. The temperature of the reaction is preferably from aboutambient temperature to about the reflux temperature of the reactionmixture. When elevated temperatures are employed, the reaction isgenerally complete in 1-4 hours.

The two carboxamide-type compounds of this invention can be preparedaccording to Scheme 2 ##STR7## where Ar' and G are the same aspreviously described, m is 0 or 1, and Z is either hydrogen or --CHR₁'R₂ .

The transformation as depicted in Scheme 2 above can be accomplished byany of several known methods of coupling carboxylic acids to amines. Forexample, carboxylic acid V or IX can be transformed into a correspondingacid halide, particularly an acid chloride, and then reacted with theappropriate amine to provide amides VII or XI. Conversion of the acid tothe corresponding acid chloride, for example, can be accomplished upontreatment with a reagent such as thionyl chloride or oxalyl chlorideoptionally in the presence of a nonreactive base and optionally in thepresence of a aprotic nonreactive solvent. Preferred combinationsinclude thionyl chloride treatment followed by reaction of the amine inpotassium carbonate in tetrahydrofuran, or reaction of oxalyl chloridewith the carboxylic acid followed by addition of the amine indimethylformamide and triethylamine. Alternatively, the oxalyl chloridereaction can be performed in the presence of sodium hydride intetrahydrofuran. The amine can also be introduced as an acid salt andadded together with a nonreactive base. Thus, the amine hydrochloridemay be added with triethylamine, pyridine, or the like.

Alternatively, other amide-condensing reagents may also be employed,such as 1,1'-carbonyldiimidazole or 1,3-dicyclohexylcarbodiimide. Thesereagents are usually employed in a nonreactive high boiling solvent suchas dimethylformamide and optionally in the presence of reagents such asdiisopropylethylamine, hydroxybenzotriazole, and the like in order tofacilitate reaction.

Ketone-containing compounds of Formula I and I' can be prepared byreacting either an anhydride of Formula XII or carboxylic acid ofFormula V with a compound of Formula XIII to provide the correspondingketones XIV and XV, respectively. ##STR8## As indicated in Scheme 3above, the anhydride method is particularly preferred for preparing thepreferred compounds of Formula Ia whereas the use of acids such asFormula V can more generally be employed.

In Scheme 3 above, R₄, G, Z, m, and Ar' are the same as previouslydefined.

The reactions portrayed in Scheme 3 are generally known asFriedel-Crafts reactions which involve reacting approximately equimolaramounts of the acid or anhydride with reagent XIII in the presence of aLewis acid, such as aluminum chloride, in a non-reactive polar solventsuch as dimethylformamide.

In a manner analogous to Scheme 3 above, preferred amide-containingcompounds of Formula I or I' can be prepared according to the followingScheme: ##STR9## According to Scheme 4, the reaction of the appropriateanhydride XII and amine VI is accomplished by mixing the two reagents inone or more nonreactive solvents, such as dimethylformamide, ethanol,mixtures of the same, etc. This reaction therefore gives productssimilar to those found in Scheme 2 above which are, in part, thepreferred compounds of Formula Ia. Alternatively, anhydride XII can bereacted with one equivalent of an alcohol to provide a monoacidmonoester of Formula V which is reacted in accordance with Scheme 2.

Another method of preparing compounds of this invention include those ofScheme 5. ##STR10## where G" is phenylene. In this sequence,intermediate XVII is acylated with an acid halide of the Formula R₂COCl. This reaction is a Friedel-Crafts reaction which is best carriedout in the presence of a Lewis acid, such as aluminium chloride, in anonreactive solvent such as dichloromethane. The resulting ketoneintermediate XVIII can then be reacted with iodine and the appropriatealkylating agent, such as trimethyl orthoformate, to introduce the R₁ 'functionality to prepare those compounds wherein n is 0. Alternatively,for compounds wherein n is 1-4, ketone intermediate XVIII can be reactedwith a Wittig reagent such as those of the general formula (CH₃ O)₂PO(CH₂)_(n-1) COO(C₁ -C₄ alkyl) or (CH₃ O)₂ PO(CH₂)_(n-1) CN to providethe corresponding ethylene derivative which can be transformed into thealkanoic ester or alkane-nitrile upon reduction of the double bond. Thisreaction sequence is particularly useful in preparing compounds whereinG is phenylene and X is --O-- or --CH₂ --. When X is --CH₂ -- and G is ahetero group, other reaction schemes such as Scheme 1, may be employed.

When G is G", the ketone-containing compounds can be prepared byreacting an intermediate such as Br--G"--Z with a lithiating reagent,such as n-butyllithium, to produce the corresponding Li--G"--Zintermediate which can be reacted with the corresponding aldehydeAr'-CHO to provide the desired intermediate XVII where X is --CO--.

The directly substituted compounds of this invention, i.e., compoundswherein X is a bond, can be prepared in a variety of ways. When G is G",the compounds are best prepared according to the procedure of Scheme V.In the case of biphenyl compounds, reaction of the ketone with iodineand trimethylorthoformate does not introduce the desired functionality.Thus, in this case, the appropriate procedure either involves the Wittigreaction described above, or, when n is 0, the ketone may be reduced tothe corresponding alcohol, for example, with sodium borohydride in thepresence of ethanol, and the resulting alcohol intermediate transformedinto the bromo derivative, upon treatment with phosphorus tribromide ina solvent such as dichloromethane. The bromo group is displaced upontreatment with cyanide, such as the treatment with sodium or potassiumcyanide, upon heating in a solvent such as dimethylsulfoxide. Thenitrile group can then be transformed into the corresponding tetrazoleor hydrolyzed to the acid as described above.

The heterocyclic compounds of this invention (G=G', X=a bond) are bestprepared by reacting the same dilithium hetero intermediate as describedabove with the appropriate derivative Ar'--Br to provide thecorresponding intermediate compound II which can then be transformed inthe usual manner.

As noted above, the compounds of this invention contain at least onechiral center, that being the carbon atom to the G, R₁, and R₂substituents. While all of the above schemes address reactions involvingracemic reagents and products, each of the reactions can be performedusing a chiral starting material to provide a particular enantiomer ofinterest. The reaction of Scheme 1 is particularly useful sinceintroduction of the chiral center is the penultimate step.Alternatively, particular isomers can be isolated from the racemate byresolution employing standard methods, such as fractionalcrystallization, high pressure liquid chromatography, and the like.These resolutions can be accomplished either on the final product I,intermediate I', at any stage along the synthetic pathway, or onderivatives of the final products and intermediates.

Compound of Formula I and I' wherein the Ar group contains an activemethylene on the α-carbon to the carbonyl, such as Ar=(C₆ H₅)₂ CH--, canbe converted to the corresponding hydroxy derivative (e.g., C₆ H₅)₂C(OH)-- upon base hydrolysis. This transformation can usually beaccomplished upon hydrolysis of an ester group of such intermediates.Thus, the preparation of such compounds wherein W hydroxy can generallybe accomplished in this manner.

The introduction of methyl or ethyl substituents in such compounds canbe accomplished by the applicable reactions above employing startingmaterials wherein Ar' has the appropriate W substituent.

In all the above schemes, it is preferred that the reactions be carriedout wherein all of the R₃ ' groups are either ester or nitrile which canthen be transformed as described above. However, as will be appreciatedby one skilled in the art, many of these reactions can be performed onthe free acid or tetrazole if the appropriate reaction conditions,blocking reagents, or the like are used. Since the nitrile and estergroups are considerably different in their sensitivity to hydrolysis,the sequence for transforming intermediates of Formula I' to finalproducts having both an acid and a tetrazole group is not critical.However, preferrably a nitrile group is transformed into a correspondingtetrazole before hydrolysis of an ester.

Intermediates II, III, V, VI, VIII, IX, XII, XIII, and XVII, and anyother reagents required for their transformation, are eithercommercially available, known in the art, or can be prepared by methodsknown in the art. In particular, intermediates such as those of FormulaVI and VIII can be prepared from the corresponding nitro compoundpreferrably by hydrogenation and are generally used immediately withoutfurther isolation. Such a transformation is best accomplished in thepresence of a catalyst, such a palladium on carbon, in an inert solventsuch as ethanol.

The nitro precursors to compounds VI and VIII can be prepared in one ofat least two ways. Either the corresponding aryl nucleus can be nitratedunder standard nitrating conditions, or the nitro compound can be firstmodified, such as introducing the R₄ substituent in the phenyl ring oralkylation of the G ring with intermediate III. Alternatively, the--CHR₁ 'R₂ sidechain can be built up sequentially, such as through thestandard alkylation of the basic intermediate, such as, for example,phenyl acetate to provide the α-alkylphenyl acetate which can then benitrated, reduced, etc.

The amino-containing compounds (R₄ is amino, acetamido, ormethanesulfonamido) can be either prepared directly by the methodsdescribed above or prepared from the corresponding nitro or aminocompounds of Formulas I or I'. For example, 3-nitrophthalic acidanhydride can be hydrogenated to prepare the corresponding3-amino-phthalic anhydride intermediate. The treatment of this aminocompound with acetyl chloride in potassium carbonate and 2-butanoneprovides the corresponding 3-acetamidophthalic anhydride intermediate.In contrast, treatment of the aminophthalic anhydride withmethanesulfonyl chloride and methane sulfonic anhydride at 100° C.provides the corresponding 3-methanesulfonamidophthalic anhydrideintermediate. Any of these anhydrides can then be employed in thecorresponding transformations as described above. Alternatively, thenitro intermediate of Formula I' can be similarly hydrogenated,sulfonylated, or acylated to provide the corresponding amino,sulfonamido, or acetamido intermediates of Formula I'.

The introduction of the various --(CH₂)_(n) R₃ ' functionalities can beintroduced either directly or through the manipulation of precursors tothat side chain. For example, an intermediate, such as a nitro precursorto compound VI, where R₁ ' is --COO(C₁ -C₄ alkyl), can be reduced to thecorresponding aldehyde or otherwise transformed to a compoundcorresponding to that of VI wherein R₁ ' is --CHO. The aldehyde can thenbe reacted with the appropriate Wittig reagent to introduce theappropriate number of carbon atoms and the carboxylic acid ester ornitrile functionality with the R₁ ' chain being unsaturated. Catalyticreduction can then be employed to provide the corresponding alkanoicester or alkylnitrile.

In some cases where G is the nitrogen heterocycle (G'), an intermediatecorresponding to Formula II can be alkylated in the same manner asprovided in Scheme 1. Thus, when G is G', intermediates VII, XI, XIV, XVand XVI can usually be transformed from compounds wherein Z is hydrogento the corresponding compounds wherein Z is --CHR₁ 'R₂ according to theprocess of Scheme 1. However, in those cases where the amino heterocycleis unstable, preparing intermediate II must be accomplished by alternatemeans. For example, if X is --CONH-- and G' is 4-imidazolyl, compound IIcannot be prepared by reacting V with 4-aminoimidazole since the latteris not stable.

In the reactions preparing compounds VII and XVI where there is acarboxylic acid functionality attached directly or through a methylenegroup to the ortho position of the phenyl ring of the Ar' group,reaction of either the acid or anhydride with amine VI may result ineither the amide VII or XVI as drawn, or may result in a ring closedphthalimide or homophthalimide intermediate which will, upon hydrolysis,ring open to the ortho-carboxylic or -acetic acid final product.

The amine containing compounds of this invention (X=--NH--) can beprepared in at least two ways. When G is phenylene, an Ullmann reactioncan be performed on an intermediate of Formula VIII and a bromocontaining compound of the Formula Br-G"--COR₂ to provide compounds ofFormula XVIII wherein X is --NH--. Typical Ullmann conditions includethe reaction of these reagents in the presence of copper bronze andcopper chloride in the presence of pyridine or dimethylformamide. Forpreparing the heterocyclic compounds of this invention, a similarreaction can be employed. In this way, intermediate VIII is reacted witha compound of the formula Br-G'-D where D is a protecting group such asa benzyl functionality. Again under Ullmann conditions, the resultingproduct is a protected form of Compound II which can then be deblocked(i.e., debenzylated) and alkylated in the usual manner. These sameschemes can be used to make the ethers (X=--O--) of this inventionbeginning with the hydroxy analog to compound VIII.

The following Examples and preparations are provided merely to furtherillustrate the invention. The scope of the invention is not construed asmerely consisting of the following Examples.

In the following Examples and preparations, melting point, nuclearmagnetic resonance spectra, mass spectra, high pressure liquidchromatography over silica gel, and N,N-dimethylformamide areabbreviated m.p., NMR, MS, HPLC, and DMF, respectively. The reportedmelting points are uncorrected. The terms "NMR" and "MS" indicate thatthe spectrum was consistent with the desired structure.

PREPARATION 1 4-Nitro-α-hexyl-1H-imidazole-1-acetic acid ethyl ester

Sixty percent sodium hydride in oil (14.8 g) was washed with hexane toremove the oil and the residue covered with DMF. A solution of 41.8 g of4-nitroimidazole was added as a solution in DMF to the sodium hydridemixture. After addition, the mixture was heated at reflux for one hour,cooled, at a solution of 92 g of ethyl 2-bromooctanoate in DMF wasadded. The mixture was heated at reflux for two hours, allowed to cool,and stirred overnight at room temperature. The mixture was added to icewater, extracted with ethyl acetate, and the combined organic extractswashed with water, dried over sodium sulfate, and concentrated in vacuoto provide 104.0 g of the desired titled intermediate, oil.

Analysis for C₁₃ H₂₁ N₃ O₄ :

Calc.: C, 55.11; H, 7.47; N, 14.83;

Found C, 54.89; H, 7.62; N 14.95.

Prepared in the same manner was4-nitro-α-hexyl-1H-imidazole-1-acetonitrile.

Analysis for C₁₀ H₁₆ N₄ O₂ :

Calc.: C, 55 92; H, 6.83; N, 23.71;

Found: C, 55.64; H, 6.72; N, 23.98.

PREPARATION 2 4-Nitro-β-hexyl-1H-imidazole-1-propanoic acid methyl ester

The title intermediate was prepared by combining 5.0 grams of4-nitroimidazole, 8.26 g of methyl 2-nonenate, 4.08 g of sodiumbicarbonate, and 200 ml of dimethylformamide and heating the mixture at80° C. for 18 hours. After cooling, the mixture was poured into waterand extracted into ethyl acetate. The organic layer was concentrated invacuo and the residue purified by HPLC over a silica column eluting withethyl acetate. The appropriate fractions were combined and concentratedin vacuo to provide 2.2 g of the desired titled intermediate.

Analysis for C₁₃ H₂₁ N₃ O₄ :

Calc.: C, 55.11; H, 7.47; N, 14.83;

Found: C, 55.37; H, 7.37; N, 14.58.

PREPARATION 3 4-Nitro-β-hexyl-1H-imidazole-2-ethanol

To 5 g of 4-nitro-α-hexyl-1H-imidazole-1-acetic acid ethyl ester in 100ml of dry methanol were added 2 molar equivalents of lithium borohydridedropwise as a solution in 70 ml of methanol. The reaction was allowed tostir at room temperature for 6 hours. The solvent was removed in vacuoto provide a white solid which was slurried in diethyl ether andfiltered to provide 2.3 g of the desired titled intermediate, m.p.83°-84° C.

Analysis for C₁₁ H₁₉ N₃ O₃ :

Calc.: C, 54.76; H, 7.94; N, 17.42;

Found: C, 54.50; H, 7.71; N, 17.36.

PREPARATION 4 4-Nitro-α-hexyl-1H-imidazole-1-acetaldehyde

To 1.3 ml of oxalyl chloride in 32 ml of dry methylene chloridepreviously cooled to -55° to -60° C. were added 2.2 ml ofdimethylsulfoxide dropwise while maintaining the temperature at -55° to-60° C. After stirring for 2 minutes, 3 g of the alcohol fromPreparation 3 above were added as a solution in 20 ml of methylenechloride dropwise over a 5 minute period. After stirring for 15 minutes,9.2 ml of triethylamine was added dropwise while maintaining thetemperature. The reaction mixture was then allowed to warm to roomtemperature and was quenched with water. The mixture was extracted withmethylene chloride and the organic layer dried over sodium sulfate andconcentrated in vacuo. The residue was purified by HPLC eluting with 1:1ethyl acetate/hexane. The appropriate fractions were combined andconcentrated to provide 800 mg of the title intermediate used directlyinto next reaction.

PREPARATION 5 4-Nitro-γ-hexyl-1H-imidazole-1-but-2-enoic acid methylester

To 800 mg of trimethyl phosphonoacetate in 50 ml of tetrahydrofurancooled to 0° C. were added 2.8 ml of 1.6M butyllithium in hexane whilemaintaining the temperature in 0° C. After stirring for 5 minutes, themixture was allowed to warm to room temperature. After once againcooling to 0° C., 700 mg of the aldehyde from Preparation 4 above wereadded dropwise as a solution in 50 ml of tetrahydrofuran. The mixturewas allowed to warm to room temperature and stirred for 2 hours. Aftercooling, the reaction was quenched with water and the reaction extractedinto ethyl acetate. The organic layer was dried over sodium sulfate,concentrated in vacuo, and the residue purified by HPLC eluting withdiethyl ether to provide 500 mg of the desired title intermediate. MS:M⁺ =295.

PREPARATION 6

Ethyl α-hexylphenyl acetate

Fifty milliters of ethyl phenylacetate were dissolved in 600 ml oftetrahydrofuran and cooled to -2° C. Over a period of 15 minutes, 13.9 gof 60% sodium hydride in oil were added in portions. To the mixture wereadded 60 ml of 1-bromohexane over a 20 minute period. Stirring wascontinued at approximately 0° C. for 1 hour and the mixture was thenallowed to warm to room temperature. The reaction was allowed to stirovernight at room temperature and was heated at reflux for 3 hours.After cooling, the mixture was added to ice water and extracted withethyl acetate. The organic layer was washed with a saturated sodiumchloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by HPLC eluting with 0-10% ethylacetatein hexane, gradient. The appropriate fractions were combined andconcentrated to provide 8.6 g of the desired title intermediate. NMR.

PREPARATION 7 Ethyl α-hexyl-4-nitrophenylacetate

Two hundred milliliters of concentrated nitric acid were cooled to 5° C.and 200 ml of concentrated sulfuric acid were slowly added. When thetemperature had returned to 5° C., 20 g of the ester from Preparation 6above were added dropwise so as to keep the temperature at 5°-6° C. Themixture was then added to one liter of ice water, and extracted withethyl acetate. The organic layers were combined, washed with water and asaturated sodium chloride solution, dried over magnesium sulfate andconcentrated in vacuo. The residue was chromatographed by HPLC elutingfirst with four liters of hexane followed by a 0-10% ethyl acetate inhexane gradient. Appropriate fractions were combined and concentrated invacuo to provide 2.7 g of the desired titled intermediate and 17 g of amixture of other products.

Analysis for C₁₆ H₂₃ NO₄ :

Calc.: C, 65.51; H, 7.90; N, 4.77;

Found: C, 65.64; H, 7.88; N, 4.85.

PREPARATION 8 4-Amino-β-hexyl-1H-imidazole-1-acetic acid ethyl ester

A mixture of 5.9 g of 4-nitro-α-hexyl-1H-imidazole-1-acetic acid ethylester, 3 g of palladium-on-carbon and 150 ml of absolute alcohol weresubjected to catalytic hydrogenation. Both theoretical and actualhydrogen uptake was 73 pounds. The catalyst was removed by filtrationand the filtrate concentrated in vacuo to provide 5.3 g of the desiredtitle intermediate which was used directly.

Prepared in like manner was ethyl α-hexyl-4-aminophenylacetate from thecorresponding nitro compound.

EXAMPLE 1α-Hexyl-4-[(1-oxo-2,2-diphenylbutyl)amino]-1H-imidazole-1-acetic acidethyl ester

Five grams of 2,2-diphenylbutanoic acid were converted to thecorresponding acid chloride by with 30 ml of thionyl chloride at refluxfor two hours. The mixture was concentrated in vacuo and the resultingacid chloride was used directly in the next step.

To a solution of 100 ml of 20% potassium carbonate solution in 100 ml oftetrahydrofuran were added, 5.3 g of4-amino-α-hexyl-1H-imidazole-1-acetic acid ethyl ester with stirring.The acid chloride prepared above was added as a solution intetrahydrofuran and the mixture heated at reflux overnight. The reactionmixture was added to ice water and extracted with ethyl acetate. Theorganic layer was separated, washed with water, dried over sodiumsulfate, and concentrated in vacuo to provide 6.0 g of the desiredtitled intermediate.

Analysis for C₂₉ H₃₇ N₃ O₃ :

Calc.: C, 73.23; H, 7.84; N, 8.83;

Found: C, 68.63; H, 7.17; N, 7.28.

EXAMPLE 24-[(3-Hydroxy-2-carboxybenzoyl)amino]-β-hexyl-1H-imidazole-1-propanoicacid methyl ester

To a solution of 2.0 g of 3-hydroxyphthalic anhydride in 250 ml ofabsolute alcohol were added 3.0 g of4-amino-β-hexyl-1H-imidazole-3-propanoic acid methyl ester. The mixturewas stirred overnight at room temperature. The resulting whiteprecipitate was recovered by filtration, washed with ethanol, and driedto provide 2.8 g of the desired titled intermediate.

Analysis for C₂₁ H₂₇ N₃ O₆ :

Calc.: C, 60.42; H, 6.52; N, 10.07;

Found: C, 60.33; H, 6.62; N, 9.88.

EXAMPLES 3-12

The following intermediates were prepared according to the procedure ofExample 2 from the appropriate anhydride in the corresponding aminederivative. In some cases, DMF or a mixture of DMF and ethanol was usedas the solvent.

3. 4-[(4-Methyl-2-carboxybenzoyl)amino]-α-hexyl-1H-imidazole-1-aceticacid methyl ester, 46% yield.

4.4-[(3-Hydroxy-2-carboxybenzoyl)amino]-α-hexyl-1H-imidazole-1-aceticacidethyl ester, 68% yield, m.p. 185° C.

Analysis for C₂₁ H₂₇ N₃ O₆ :

Calc. C, 60.42; H, 6.52; N, 10.07;

Found: C, 60.60; H, 6.43; N, 10.12.

5. 4-[(2-Carboxybenzoyl)amino]-α-hexyl-1H-imidazole-1-acetic acid ethylester, 46% yield, m.p. 142°-143° C.

Analysis for C₂₁ H₂₇ N₃ O₅ :

Calc.: C, 62.83; H, 6.78; N, 10.47;

Found: C, 63.11; H, 6.85; N, 10.43.

6. α-Hexyl-4-{[(2-carboxyphenyl)acetyl]-amino}-1H-imidazole-1-aceticacid ethyl ester, 8.6% yield.

7.α-Hexyl-4-{[(2-carboxy-1-naphthalenyl)-carbonyl]amino}-1H-imidazole-1-aceticacid ethyl ester, 34% yield, m.p.=116°-118° C. NMR

8. 4-[(2-Carboxy-6-fluorobenzoyl)amino]-α-hexyl-1H-imidazole-1-aceticacid ethyl ester, 27% yield.

Analysis for C₂₁ H₂₆ FN₃ O₅

Calc.: C, 60.13; H, 6.24; N, 10.01;

Found: C, 60.67; H, 6.40; N, 9.90.

9. 4-[(2-Carboxybenzoyl)amino]-α-hexylbenzene-acetic acid ethyl ester,15% yield, m.p.=155°-156° C..

Analysis for C₂₄ H₂₉ NO₅ :

Calc.: C, 70.05; H, 7.10; N, 3.40;

Found: C, 69.77; H, 6.99; N, 3.29.

10. 4-[(2-Carboxybenzoyl)amino]-β-hexyl-1H-imidazole-1-propanoic acidmethyl ester, 42.3% yield, m.p.=125°-127° C.

Analysis for C₂₁ H₂₇ N₃ O₅ :

Calc. C, 62.83; H, 6.78; N, 10.47;

Found: C, 62.85; H, 6.78; N, 10.30.

11. α-Hexyl-4-[(2-carboxy-6-nitrobenzoyl)amino]-1H-imidazole-1-aceticacid ethyl ester, 95% yield. NMR.

12. 4-[(2-Carboxybenzoyl)amino]-α-hexyl-1H-imidazole-1-acetonitrile,72.1% yield, m.p. 170°-171° C.

Analysis for C₁₉ H₂₂ N₄ O₃ :

Calc.: C, 64.39; H, 6.26; N, 15.81;

Found: C, 64.31; H, 6.07; N, 15.82.

EXAMPLE 13 4-[(2-Carboxybenzoyl)amino]-γ-hexyl-1H-imidazole-1-butanoicacid methyl ester

Five hundred milligrams of 4-nitro-γ-hexyl-1H-imidazole-4-non-2-enoicacid methyl ester were hydrogenated in the presence of 500 mg of 5% ofpalladium-on-carbon and 200 ml of absolute ethanol according to theprocedure of Preparation 8. Hydrogenation reduced the nitro group to anamino group and also hydrogenated the double bond. The catalyst wasremoved by filtration and the resulting solution was treated with 150 mgof phthalic anhydride. After stirring at room temperature for 24 hours,the solvent was removed in vacuo and the resulting solid partitionedbetween ethyl acetate and water. The organic layer was separated, driedover sodium sulfate, and concentrated in vacuo. Trituration with a 1:1mixture of hexane/ethyl acetate provided 270 mg of the desired titledintermediate, m.p. 135°-136° C.

Analysis for C₂₂ H₂₉ N₃ O₅ :

Calc.: C, 63.60; H, 7.04; N, 10.11;

Found: C, 63.66; H, 6.92; N, 9.96.

EXAMPLE 14α-Hexyl-4-[(diphenylhydroxyacetyl)amino]-1H-imidazole-1-acetic acidethyl ester

A mixture of 4.6 g of benzilic acid, 3.2 g of 1,1'-carbonyldiimidazole,and 150 ml of DMF were mixed and stirred for 1 hour. A solution of 5.0 gof 4-amino-α-hexyl-1H-imidazole-1-acetic acid ethyl ester in DMF wasadded and the mixture stirred at room temperature over-night. Thereaction mixture was concentrated in vacuo, ethyl acetate was added, andthe organic solution was washed sequentially with water, a 10% sodiumhydroxide solution, and water. The organic layer was dried over sodiumsulfate and concentrated in vacuo. The residue was purified by HPLCeluting with 30% ethyl acetate in toluene. The appropriate fractionswere combined and concentrated in vacuo to provide 1.4 g of the desiredtitled product.

Analysis for C₂₇ H₃₃ N₃ O₄ :

Calc.: C, 69.96; H, 7.17; N, 9.06;

Found: C, 70.22; H, 7.01; N, 8.82.

EXAMPLES 15-20

The following compounds were prepared according to the procedure ofExample 14 employing the appropriate carboxylic acid and thecorresponding amine.

15. 4-[(9H-Fluoren-9-ylcarbonyl)amino]-αhexyl-1H-imidazole-1-acetic acidethyl ester, 22% yield, m.p. 150°-152° C.

Analysis for C₂₆ H₃₁ N₃ O₃ :

Calc.: C, 72.78; H, 7.01; N, 9.43;

Found: C, 72.85; H, 6.95; N, 9.22.

16. α-Hexyl-4-[(9H-xanthen-9-ylcarbonyl)amino]-1H-imidazole-1-aceticacid ethyl ester, 9.5% yield, m.p.=177°-178° C.

Analysis for C₂₇ H₃₁ N₃ O₄ :

Calc.: C, 70.28; H, 6.72; N, 9.11;

Found: C, 70.21; H, 6.90; N, 9.12.

17. α-Hexyl-4-[(2-hydroxy-5-carboxybenzoyl)amino]-1H-imidazole-1-aceticacid ethyl ester, 24% yield, oil.

Analysis for C₂₃ H₃₁ N₃ O₆ :

Calc.: C, 62.00; H, 7.01; N, 9.43;

Found: C, 60.28; H, 7.15; N, 10.10.

18. 4-[(9H-Fluoren-9-ylcarbonyl)amino]-α-hexylbenzeneacetic acid ethylester, 42% yield, m.p. 174°-175° C.

Analysis for C₃₀ H₃₃ NO₃ :

Calc.: C, 79.09; H, 7.30; N, 3.07;

Found: C, 79.29; H, 7.24; N, 3.04.

19. α-Hexyl-3-{[(diphenylmethyl)amino]-carbonyl}phenylacetonitrile, 60%yield, m.p. 125°-128° C.

Analysis for C₂₈ H₃₀ N₂ O:

Calc.: C, 81.91; H, 7.36; N, 6.82;

Found: C, 81.22; H, 7.16; N, 6.21.

20. α-Hexyl-4-{[2-(5-tetrazolyl)benzoyl]amino}-1H-imidazole-1-aceticacid ethyl ester, 18% yield.

Analysis for C₂₁ H₂₇ N₇ O₃ :

Calc.: C, 58.54; H, 5.85; N, 23.90;

Found: C, 58.39; H, 6.31; N, 23.44.

EXAMPLES 21-22

The following esters were prepared according to the procedure of Example14 from the appropriate carboxylic acid and the corresponding amineemploying N,N'-dicyclohexylcarbodiimide and hydroxybenzotriazole hydratein place of the carbonyldiimidazole.

21.4-{[2-(Ethoxycarbonylmethyl)benzoyl]-amino}-α-hexyl-1H-imidazole-1-aceticacid ethyl ester, 40% yield, oil.

Analysis for C₂₄ H₃₃ N₃ O₅ :

Calc.: C, 64.99; H, 7.49; N, 9.47;

Found: C, 65.25; H, 7.83; N, 9.28.

22.α-Hexyl-4-[(2-ethoxycarbonyl-3-nitrobenzoyl)amino]-1H-imidazole-1-aceticacid ethyl ester, 70% yield, m.p. 125°-127° C., MS: M⁺ =474.

Analysis for C₂₃ H₃₀ N₄ O₇ :

Calc.: C, 58.23; H, 6.37; N, 11.81;

Found: C, 58.64; H, 6.15; N, 11.76.

PREPARATION 9 N-(Diphenylmethyl)-1H-imidazole-4-carboxamide

A mixture of 11.7 g of 4-imidazolecarboxylic acid, 18.7 g of1,1'-carbonyldiidmidazole, 20 ml of diisopropylethylamine and 600 ml ofDMF was heated at 35° C. for approximately 18 hours. Twenty milliters ofaminodiphenylmethane were added and the solution stirred at 35° C. forapproximately 21/2 days. The mixture was concentrated in vacuo and theresidue added to 400 ml of water. The mixture was extracted with ethylacetate and the organic layer was washed with a saturated sodiumchloride solution, dried over magnesium sulfate, and concentrated invacuo. Two crystallizations from hot ethyl acetate/hexane provided 11grams of the desired titled intermediate, m.p. 201°-202° C.

Analysis for C₁₇ H₁₅ N₃ O:

Calc.: C, 73.63; H, 5.45; N, 15.15;

Found: C, 73.90; H, 5.58; N, 15.12.

EXAMPLE 23α-Hexyl-4-{[(9H-fluoren-9-yl)amino]carbonyl}-1H-imidazole-1-acetic acidethyl ester

A slurry of 0.062 g of 55% sodium hydride in oil in tetrahydrofuran wasadded to 0.4 g of 4-carboxy-α-hexyl-1H-imidazole-1-acetic acid ethylester. After 10 minutes of stirring, 0.125 ml of oxalyl chloride wereadded. After stirring for 2 hours at room temperature, 0.31 g of1-aminofluorene were added followed by 0.16 ml of pyridine. The mixturewas stirred at room temperature for 3 hours, taken up in ethyl acetate,and washed twice with a saturated citric acid solution followed by awater wash. The organic layer was dried over sodium sulfate, filtered,and concentrated in vacuo. Flash chromatography using 1:1 ethylacetate/hexane and silica gel was performed on the residue and theresulting fractions combined and concentrated in vacuo to provide thedesired titled intermediate.

EXAMPLE 24α-Hexyl-4-{[(diphenylmethyl)amino]carbonyl{-1H-imidazole-1-acetonitrile

To a solution of 1.67 g of4-{[(diphenylmethyl)amino]carbonyl}-1H-imidazole in 100 ml ofdimethylformamide were added 5.03 g of potassium fluoride on alumina.With stirring, 1.35 g of α-bromooctanonitrile were added. The solutionwas stirred at room temperature overnight and then concentrated invacuo. The residue was taken up in ethyl acetate, washed with water,washed with a saturated sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. NMR indicated a mixture of startingmaterial with desired product, so the residue was dissolved in 200 ml ofacetonitrile, and 1 g of α-bromooctanonitrile and 5 g of potassiumfluoride on alumina was added. After stirring at room temperature for 2days, the mixture was filtered, and the filtrate was concentrated invacuo. The residue was chromatographed over SiO₂ and the appropriatefractions combined and concentrated in vacuo to provide 1.2 g of thedesired titled intermediate, oil. MS: M⁺ =400.

Analysis for C₂₅ H₂₈ N₄ O:

Calc.: C, 74,97; H, 7.05; N, 13.99;

Found: C, 74.28; H, 6.82; N, 13.29.

EXAMPLE 25

5-Phthalimido-α-hexyl-2H-tetrazole-2-acetic acid ethyl ester

A. Preparation of 5-[(2-ethoxycarbonylbenzoyl)amino]tetrazole.

To 50 g of oxalyl chloride were added 16.1 g of phthalic acidmonomethylester. After stirring at room temperature for 2 hours, themixture was concentrated in vacuo. The residue was added dropwise to amixture of 9.2 g of 5-aminotetrazole, 12 ml of triethylamine, and 150 mlof DMF. After stirring for 2 hours at room temperature the mixture wasfiltered and the filtrate concentrated in vacuo. The resulting whitesolid was partitioned between water and ethyl acetate. The aqueous phasewas made acidic to pH 2 and the two layers stirred overnight. Theremaining white solid was recovered by filtration and dried to provide12 g of the desired subtitled intermediate, m.p. 257° C.(decomposition).

Analysis for C₁₀ H₉ N₅ O₃ :

Calc.: C, 48.59; H, 3.67; N, 28.33;

Found: C, 48.37; H, 3.71; N, 28.55.

B. Preparation of 5-phthalimido-α-hexyl-2H-tetrazole-2-acetic acid ethylester.

A mixture of 5 g of the tetrazole amide from Example 25A above, 5.6 g ofethyl 2-bromooctanoate, 3.4 g of sodium bicarbonate, and 200 ml of DMFwas heated at 75° C. for 2.5 hours. The solution was allowed to cool toroom temperature and then concentrated in vacuo. The residue waspartitioned between water and ethyl acetate and the aqueous layeradjusted to pH 2.5 with 1N hydrochloric acid. The solution was extractedtwice with ethyl acetate. The organic layers were combined, washed withwater and a saturated sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The resulting solid was trituratedwith diethyl ether. The ether was separated filtered, and concentratedto provide 6.5 g of an oil which contained both the N-1 and N-2 isomers.This material was purified by HPLC using a 0-60% ethyl acetate in hexanegradient to provide 3.4 g of the desired N-2 isomer and 0.6 g of theundesired N-1 isomer, oil. NMR.

EXAMPLE 26α-Hexyl-4-[(1-oxo-2,2-diphenylbutyl)amino]-1H-imidazole-1-acetic acid

A mixture of 6 g ofα-hexyl-4-[(1-oxo-2,2-diphenylbutyl)amino]-1H-imidazole-1-acetic acidethyl ester, 50 ml of 1N sodium hydroxide, and 100 ml of methanol werestirred at room temperature for 1 hour. The mixture was concentrated invacuo, taken up in water, and the pH adjusted to 4.0. The aqueoussolution was extracted with ethyl acetate. The organic extract waswashed twice with water, dried over sodium sulfate, and concentrated invacuo. The residue was dissolved in methylene chloride, filtered, andconcentrated in vacuo to provide 2.4 g of the desired titled product.

Analysis for C₂₇ H₃₃ N₃ O₃ : Calc.: C, 72.46; H, 7.43; N, 9.39; Found:C, 72.20; H, 7.50; N, 9.39.

EXAMPLES 27-45

The following acids were prepared according to the procedure of Example26 employing the appropriate ester intermediate; in some cases,potassium hydroxide was used in place of sodium hydroxide. Thehydrochloride salts were formed by dissolving the acid in ethyl acetate,adding 10% hydrochloric acid, and removing the salt by filtration.

27.β-Hexyl-4-[(2-carboxy-3-hydroxybenzoyl)amino]-1H-imidazole-1-propanoicacid hydrate, 86% yield.

Analysis for C₂₀ H₂₅ N₃ O₆.H₂ O: Calc.: C, 58.00; H, 6.46; N, 9.97;Found: C, 58.01; H, 6.03; N, 9.89.

28. α-Hexyl-4-[(2-carboxy-4-methylbenzoyl)amino]-1H-imidazole-1-aceticacid, 27% yield.

Analysis for C₂₀ H₂₅ N₃ O₅ : Calc.: C, 62.00; H, 6.50; N, 10.85; Found:C, 61.77; H, 6.39; N, 10.69.

29. α-Hexyl-[(hydroxydiphenylacetyl)amino]-1H-imidazole-1-acetic acidhydrochloride, 57% yield.

Analysis for C₂₅ H₂₉ N₃ O₄.HCl: Calc.: 63.62; H, 6.41; N, 8.90; Found:C, 63.41; H, 6.27; N, 8.80.

30. α-Hexyl-4-[(2-carboxy-3-hydroxybenzoyl)amino]-1H-imidazole-1-aceticmonohydrate, 20% yield.

Analysis for C₁₉ H₂₃ N₃ O₆.H₂ O: Calc.: C, 55.96; H, 6.10; N, 10.32;Found: C, 55.84; H, 5.66; N, 10.29.

31. α-Hexyl-9-[(9H-fluoren-9-ylcarbonyl)amino]-1H-imidazole-1-aceticacid hydrochloride, 60% yield.

Analysis for C₂₅ H₂₇ N₃ O₃.HCl: Calc.: C, 66.23; H, 6.18; N, 9.27;Found: C, 66.34; H, 6.19; N, 9.27.

32. α-Hexyl-4-[(9H-xanthen-9-ylcarbonyl)amino]-1H-imidazole-1-aceticacid hydrochloride monohydrate, 55% yield, m.p. 185°-188° C.

Analysis for C₂₅ H₂₇ N₃ O₄.HCl.H₂ O: Calc.: C, 61,53; H, 6.20; N, 8.61;O, 16.36; Cl, 7.27; Found: C, 61.45

33. 4-[(2-Carboxybenzoyl)amino]-α-hexyl-1H-imidazole-1-acetic acid, 35%yield.

Analysis for C₁₉ H₂₃ N₃ O₅ : Calc.: C, 61.12; H, 6.21; N, 11.25; Found:C, 61.12; H, 5.93; N, 11.01.

34. α-Hexyl-4-{[(2-carboxyphenyl)acetyl]-amino}-1H-imidazole-1-aceticacid hydrate, 3.5% yield.

Analysis for C₂₀ H₂₅ N₃ O₅.H₂ O: Calc.: C, 59,11; H, 6.65; N, 10.34;Found: C, 59.41; H, 6.35; N, 10.14.

35.α-Hexyl-4-{[(2-carboxy-1-naphthalenyl)carbonyl]amino}-1H-imidazole-1-aceticacid, 24% yield.

Analysis for C₂₃ H₂₅ N₃ O₅ : Calc.: C, 64.24; H, 5.95; N, 9.92; Found:C, 64.96; H, 6.07; N, 10.16.

36. α-Hexyl-4-[(2-hydroxy-5-carboxybenzoyl)amino]-1H-imidazole-1-aceticacid, 64% yield.

Analysis for C₁₉ H₂₃ N₃ O₆ : Calc.: C, 58.60; H, 5.95; N, 10.79; Found:C, 58.39; H, 5.76; N, 10.55. 7.27; Found: C, 61.45; H, 6.33; N, 7.87; O,15.90; Cl, 6.53.

37. 4-[(2-Carboxy-6-fluorobenzoyl)amino]-α-hexyl-1H-imidazole-1-aceticacid hydrate (1:2.5), 76% yield.

Analysis for C₁₉ H₂₂ N₃ FO₅.2.5 H₂ O: Calc.: C, 52.28; H, 6.23; N, 9.62;Found: C, 52.52; H, 6.16; N, 9.16.

38. α-Hexyl-4-[(2-carboxybenzoyl)amino]benzeneacetic acid, 35% yield,m.p. 159°-161° C.

Analysis for C₂₂ H₂₅ NO₅ : Calc.: C, 68.91; H, 6.57; N, 3.65; Found: C,68.62; H, 6.48; N, 3.53.

39. 4-[(2-Carboxybenzoyl)amino]-β-hexyl-1H-imidazole-1-propanoic acidmonohydrate, 82.5% yield, m.p. 98°-100° C.

Analysis for C₂₀ H₂₅ N₃ O₅.H₂ O:

Calc.: C, 59.24; H, 6.71; N, 10.36;

Found: C, 59.49; H, 6.36; N, 10.26.

40. α-Hexyl-4-[(2-carboxy-6-nitrobenzoyl)-amino]-1H-imidazole-1-aceticacid, 16% yield, m.p. 161°-163° C.

Analysis for C₁₉ H₂₂ N₄ O₇ :

Calc.: C, 54.54; H, 5.30; N, 13.39;

Found: C, 54.39; H, 5.24; N, 13.12.

41. 4-[(2-Carboxybenzoyl)amino]-γ-hexyl-1H-imidazole-1-butanoic acidhemihydrate, 75% yield, m.p. 83°-85° C.

Analysis for C₂₁ H₂₇ N₃ O₅.0.5H₂ O:

Calc.: C, 61.45; H, 6.88; N, 10.24;

Found: C, 61.60; H, 6.60; N, 10.25.

42. α-Hexyl-4-{[2-(tetrazol-5-yl)benzoyl]-amino}-1H-imidazole-1-aceticacid monohydrate, 10% yield. NMR, MS.

Analysis for C₁₉ H₂₃ N₇ O₃.H₂ O:

Calc.: C, 55.10; H, 5.36; N, 25.00;

Found: C, 55.42; H, 5.80; N, 22.72.

43. 4-{[2-(Carboxymethyl)benzoyl]amino}-α-hexyl-1H-imidazole-1-aceticacid monohydrate, 14% yield.

Analysis for C₂₀ H₂₅ N₃ O₅.H₂ O:

Calc.: C, 59.16; H, 6.64; N, 10.34;

Found: C, 58.81; H, 6.21; N, 10.49.

44. α-Hexyl-4-{[(9H-fluoren-9-yl)amino]-carbonyl}-1H-imidazole-1-aceticacid hydrochloride, 73% yield.

Analysis for C₂₅ H₂₇ N₃ O₃.HCl:

Calc.: C, 66.14; H, 6.22; N, 9.26;

Found: C, 67.80; H, 6.76; N, 9.37.

45. α-Hexyl-4-[(2-carboxy-3-nitrobenzoyl)-amino]-1H-imidazole-1-aceticacid hydrate, 30% yield, m.p. 151°-153° C.

Analysis for C₁₉ H₂₂ N₄ O₇.H₂ O:

Calc.: C, 52.29; H; 5.54; N, 12.84;

Found: C, 52.30; H, 5.06; N, 12.50.

EXAMPLE 46α-Hexyl-4-[(9-hydroxy-9H-fluoren-9-ylcarbonyl)-amino]benzeneacetic acid

The titled product was prepared in 76% yield fromα-hexyl-4-[(9H-fluoren-9-ylcarbonyl)amino]benzene acetic acid ethylester according to the procedure of Example 26, m.p. 183°-185° C.

Analysis for C₂₈ H₂₉ NO₄ :

Calc.: C, 75.82; H, 6.59; N, 3.16;

Found: C, 75.71; H, 6.62; N, 3.07.

EXAMPLE 47 5-[(2-Carboxybenzoyl)amino]-α-hexyl-2H-tetrazole-2-aceticacid

The titled product was prepared in 41% yield fromα-hexyl-5-phthalimido-2H-tetrazole-2-acetic acid ethyl ester accordingto the procedure of Example 26, m.p. 140°-142° C.

Analysis for C₁₇ H₂₁ N₅ O₅ :

Calc.: C, 54.39; H, 5.64; N, 18.66;

Found: C, 54.49; H, 5.69; N, 18.43.

EXAMPLE 481-[1-(Tetrazol-5-yl)heptyl]-N-(diphenylmethyl)-1H-imidazole-4-carboxamide

To a solution of 1.22 g of4-{[(diphenylmethyl)amino]carbonyl}-α-1H-imidazole-1-acetonitrile in 175ml of dimethoxyethylene were added 1.11 g of sodium azide and 2.22 g oftriethylamine hydrochloride. The mixture was heated at reflux for 21hours under a nitrogen atmosphere. The reaction was allowed to cool, thesolid was removed by filtration, and the filtrate was concentrated invacuo. The resulting oil was dissolved in methanol and methanolichydrogen chloride was added. After 30 minutes, the solvent wasevaporated. The residue was taken up in hot ethyl acetate and filtered.The filtrate was evaporated and the residue dissolved in diethyl ether,layered with water, and the pH adjusted to 8.0 with 1N sodium hydroxide.The organic layer was washed with a saturated sodium chloride solution,dried over magnesium sulfate, and concentrated in vacuo to provide 0.3 g(11%) of the titled product as a glass-like solid. MS: M⁺ =444.

Analysis for C₂₅ H₂₉ N₇ O:

Calc.: C, 67.70; H, 6.59; N, 22.11:

Found: C, 67.71: H, 6.34: N, 21.93.

EXAMPLE 49 N-(Diphenylmethyl)-3-[1-(tetrazol-5-yl)-heptyl]benzamide

The titled product was prepared in 35% yield from the correspondingnitrile intermediate according to the procedure of Example 48, m.p.198°-200° C.

Analysis for C₂₈ H₃₁ N₅ O:

Calc.: C, 74.14; H, 6.89; N, 15.44;

Found: C, 73.94; H, 6.70; N, 15.20.

EXAMPLE 502-[({1-[1-(Tetrazol-5-yl)heptyl]-1H-imidazol-4-yl}amino)carbonyl]benzoicacid hemihydrate

To 700 mg ofα-hexyl-4-[(2-carboxybenzoyl)-amino]-1H-imidazole-1-acetonitrile wereadded 2.0 g of tributyl tin azide. The mixture was heated at 85° C. for2 days, cooled, and added to 50 ml of methanol previously saturated withhydrogen chloride gas. After stirring for 20 minutes, the solvent wasremoved in vacuo. The residue was triturated with diethyl ether. Theremaining solid was diluted with 100 ml of absolute ethanol and 100 mlof 4N sodium hydroxide. After stirring for two hours, the solution wasconcentrated in vacuo. The residue was taken up in water and the pHadjusted to 3.7. The aqueous solution was extracted with ethyl acetate.The organic layer was dried over sodium sulfate and concentrated invacuo. The resulting solid was slurried with diethyl ether and filteredto provide 150 mg of the desired titled product, m.p. 120°-121° C.

Analysis for C₁₉ H₂₃ N₇ O₃.0.5H₂ O:

Calc.: C, 56.15; H, 5.95, N, 24.10;

Found: C, 56.12; H, 5.84, N, 23.97.

Example 51 α-Hexyl-4-[(diphenylacetyl)amino]-1H-imidazole-1-acetic acidhydrochloride

Following the procedure of Example 14, 637 mg of diphenylacetic acid and486 mg of carbonyldiimidazole were allowed to react in 10 ml of DMF.After stirring at room temperature for 60 minutes, 750 mg of4-amino-α-hexyl-1H-imidazole-1-acetic acid ethyl ester were added as asolution in 10 ml of DMF. The reaction was stirred overnight at roomtemperature, concentrated in vacuo, and worked up in the usual manner.The resulting ester was then hydrolyzed according to the procedure ofExample 26 to provide 250 mg of the desired titled product.

Analysis for C₂₅ H₂₉ N₃ O₃.HCl:

Calc.: C, 65.85; H, 6.63; N, 9.22;

Found: C, 69.35; H, 7.80; N, 10.32.

EXAMPLE 52α-Hexyl-3-{[(diphenylmethyl)amino]carbonyl}-1H-1,2,4-triazole-1-aceticacid hydrochloride

Following the general procedure of Example 25B, 1.2 g of3-{[(diphenylmethyl)amino]carbonyl}-1H-1,2,4-triazole in 30 ml of DMFwere treated with 0.93 ml of ethyl 2-bromooctanoate and 188 mg of 55%sodium hydride. After stirring at room temperature overnight, thereaction was worked up in the usual manner. The resulting ester washydrolyzed according to the procedure of Example 26 to provide 300 mg ofthe desired titled product.

Analysis for C₂₄ H₂₈ N₄ O₃.HCl:

Calc.: C, 68.55; H, 6.71; N, 13.3;

Found: C, 66.91; H, 6.71; N, 12.75.

EXAMPLES 53 and 54

The following compounds were prepared in the same manner as described inExample 52 beginning with the appropriate heterocyclic amide.

53. 3-{[(Diphenylmethyl)amino]carbonyl}-α-hexyl-1H-pyrrole-1-aceticacid, 48% yield.

Analysis for C₂₆ H₃₀ N₂ O₃ :

Calc.: C, 73.86; H, 7.44; N, 6.89;

Found: C, 74.37; H, 7.08; N, 6.45.

54. 4-{[(Diphenylmethyl)amino]carbonyl}-α-hexyl-1H-pyrazole-1-aceticacid, 68% yield.

Analysis for C₂₅ H₂₉ N₃ O₃ :

Calc.: C, 71.75; H, 6.97; N, 11.40;

Found: C, 71.23; H, 7.10; N, 10.04.

EXAMPLE 55 α-Pentyl-4-(2-carboxyphenoxy)phenylacetic acid

A. Preparation of 4-(2-ethoxycarbonylphenoxy)-phenylheptanone.

To a mixture of 55 g of ethyl 2-phenoxybenzoate and 35 ml of heptanoylchloride were added 35 g of aluminum trichloride. After heating atreflux for 16 hours, an additional 60 g of aluminum chloride were addedand the reaction heated at reflux an additional 16 hours. The reactionmixture was poured over ice and concentrated hydrochloric acid. Theorganic layer was separated, dried, and concentrated in vacuo. Theresidue was purified by HPLC eluting with 5-25% ethyl acetate in hexane.The appropriate fractions were combined and concentrated in vacuo toprovide 11.2 g of the desired subtitled intermediate, m.p. 54°-55° C.

Analysis for C₂₂ H₂₆ O₄ :

Calc.: C, 74.55; H, 7.39;

Found: C, 74.84; H, 7.46.

B. Preparation of α-pentyl-4-(2-ethoxycarbonylphenoxy)phenylacetic acidmethyl ester.

To 5.3 g of the ketone intermediate from Example 55A above in 8 ml oftrimethylorthoformate were added 7.62 g of iodine. The reaction mixturewas stirred at room temperature for 24 hours at which time an additional2 ml of trimethoxyorthoformate were added. After stirring an additional24 hours, aqueous 10% sodium thiosulfate was added. After stirring forone hour, the product was extracted into ethyl acetate. The organiclayer was dried, concentrated in vacuo to provide 5.2 g of the desiredsubtitled intermediate.

Analysis for C₂₃ H₂₈ O₅ :

Calc.: C, 71.85; H, 7.34;

Found: C, 71.65; H, 7.40.

C. Preparation of α-pentyl-4-(2-carboxyphenoxy)phenylacetic acid.

Following the procedure of Example 26, 4 g of the ester intermediatefrom Example 55B above were heated with ethanol and sodium hydroxidesolution to provide 2.7 g of the desired titled product, m.p. 112°-113°C.

Analysis for C₂₀ H₂₂ O₅ :

Calc.: C, 70.16; H, 6.48;

Found: C, 70.25; H, 6.58.

EXAMPLE 56 α-Hexyl-4-(2-carboxybenzoyl)benzeneacetic acid

The ethyl ester of the titled product was prepared in 18% yield byreacting phthalic anhydride and α-hexylbenzeneacetic acid ethyl ester inthe presence of aluminum chloride in DMF according to the generalprocedure of Example 55. The title product was then prepared accordingto the procedure of Example 26 in 45% yield from the intermediate ester,m.p. 118°-121° C.

Analysis for C₂₂ H₂₄ O₅ :

Calc.: C, 71.72; H, 6.56;

Found: C, 71.57; H, 6.32.

EXAMPLES 57-58

The following products were prepared according to the procedure ofExample 14 by first reacting ethyl4-carboxy-α-hexyl-1H-imidazole-1-acetate and carbonyldiimidazole indimethylformamide together with the appropriate amine to provide thecorresponding ester intermediate which was then hydrolyzed according tothe procedure of Example 26 to provide the final products as indicated.

57.4-{[(2,3-Dihydro-1H-inden-1-yl)amino]-carbonyl}-α-hexyl-1H-imidazole-1-aceticacid hydrochloride, 83% yield.

Analysis for C₂₁ H₂₇ N₃ O₃.HCl:

Calc.: C, 62.14; H, 6.95; N, 10.35;

Found: C, 62.35; H, 7.17; N, 10.18.

58. 4-{[(Diphenylmethyl)amino]carbonyl}-α-hexyl-1H-imidazole-1-aceticacid hydrochloride, 64% yield.

Analysis for C₂₅ H₂₉ N₃ O₃.HCl:

Calc.: C, 65.85; H, 6.63; N, 9.22;

Found: C, 65.97; H, 6.51; N, 9.43.

EXAMPLE 59α-Hexyl-4-[(9-hydroxy-9H-fluoren-9-ylcarbonyl)-amino]-1H-imidazole-1-aceticacid

When 2.1 g ofα-hexyl-4-[(9H-fluoren-9-yl-carbonyl)amino]-1H-imidazole-1-acetic acidethyl ester was heated with 3.0 g of potassium hydroxide, 30 ml ofmethanol, and 15 ml of water at reflux for one hour, upon adjustment ofpH to 3.8, a thick oil formed. The oil was dissolved in ethyl acetateand separated from the aqueous layer. The organic layer was dried andconcentrated in vacuo. The oil was taken up in ethanol and saturatedwith hydrogen chloride gas. The resulting product was purified by highpressure liquid chromatography to provide 0.370 g of the titled product,m.p. 128° C.

Analysis for C₂₅ H₂₇ N₃ O₄ :

Calc.: C, 69.27; H, 6.28; N, 9.69;

Found: C, 69.03; H, 6.37; N, 9.43.

EXAMPLE 602-[({1-[1-(Hydroxymethyl)hexyl]-1H-imidazol-4-yl}amino)carbonyl]benzoicacid

Seven hundred milligrams of 4-nitro-β-hexyl-1H-imidazole-2-ethanol in100 ml of absolute ethanol and 200 mg of 5% palladium-on-carbon werehydrogenated. The reaction mixture was filtered and added directly to astirred solution of 473 mg of phthalic anhydride in 50 ml of absoluteethanol and 10 ml of dimethylformamide. The reaction was stirred at roomtemperature overnight. The solvent was removed in vacuo and diluted in100 ml of 1N sodium hydroxide solution. After stirring for 30 minutes,the mixture was washed with diethyl ether. The aqueous layer wasadjusted to pH 3.5 with 6N hydrochloric acid. The aqueous solution wasextracted into ethyl acetate. The organic layer was dried over sodiumsulfate, and concentrated in vacuo to provide 1.0 g of the desired titleproduct, m.p. 99°-101° C.

Analysis for C₁₈ H₂₃ N₃ O₄ :

Calc.: C, 62.59; H, 6.71; N, 12.16;

Found: C, 62.45; H, 6.71; N, 11.89.

EXAMPLE 61-65

The following benzamide intermediates were prepared according to theprocedure of Examples 21-22.

61. α-Hexyl-4-[(2-hydroxybenzoyl)amino]-1H-imidazole-1-acetic acid ethylester, 46% yield.

Analysis for C₂₀ H₂₇ N₃ O₄ :

Calc.: C, 64.32; H, 7.28; N, 11.25;

Found: C, 64.31; H, 7.77; N, 11.79.

62.α-Hexyl-4-{[(2-hydroxy-1-naphthalenyl)-carbonyl]amino}imidazole-1-aceticacid ethyl ester.

63. α-Hexyl-4-[(3-hydroxybenzoyl)amino]-1H-imidazole-1-acetic acid ethylester, 93% yield. MS.

64. α-Hexyl-4-[(3,4-dihydroxybenzoyl)amino]-1H-imidazole-1-acetic acidethyl ester, 37% yield.

Analysis for C₂₀ H₂₇ N₃ O₅ :

Calc.: C, 61.68; H, 6.99; N, 10.79;

Found: C, 59.70; H, 6.04; N, 13.38.

65. α-Hexyl-4-[(3,5-dihydroxybenzoyl)amino]-1H-imidazole-1-acetic acidethyl ester, 58% yield.

Analysis for C₂₀ H₂₇ N₃ O₅ :

Calc.: C, 61.68; H, 6.99; N, 10.79;

Found: C, 58.68; H, 6.64; N, 11.91.

EXAMPLES 66-75

The following imidazole carboxamide derivatives were prepared from theappropriate imidazole carboxylic acid and corresponding anilinederivative according to the procedure of Examples 14 and 47-58 above.

66.α-Hexyl-4-({[(4-hydroxyphenyl)methyl]-amino}carbonyl)-1H-imidazole-1-aceticacid ethyl ester.

67. α-Hexyl-4-{[(2-hydroxyphenyl)amino]-carbonyl}-1H-imidazole-1-aceticacid ethyl ester.

68.α-Hexyl-4-({[2-(hydroxymethyl)phenyl]-amino}carbonyl)-1H-imidazole-1-aceticacid ethyl ester.

69.α-Hexyl-4-({[2-(4-hydroxybutyl)phenyl]-amino}carbonyl)-1H-imidazole-1-aceticacid ethyl ester.

70.α-Hexyl-4-({[3-(hydroxymethyl)phenyl]-amino}carbonyl)-1H-imidazole-1-aceticacid ethyl ester.

71.α-Hexyl-4-({[2-(2-hydroxyethyl)phenyl}-amino}carbonyl)-1H-imidazole-1-aceticacid ethyl ester.

72.α-Hexyl-4-({[(4-(2-hydroxyethyl)phenyl]-amino}carbonyl)-1H-imidazole-1-aceticacid ethyl ester.

73. α-Butyl-4-{[(4-hydroxyphenyl)amino]-carbonyl}-1H-imidazole-1-aceticacid ethyl ester.

74. α-Butyl-4-{[(3-hydroxyphenyl)amino]-carbonyl}-1H-imidazole-1-aceticacid ethyl ester.

75. α-Butyl-4-{[(2-hydroxyphenyl)amino]-carbonyl}-1H-imidazole-1-aceticacid ethyl ester.

EXAMPLES 76-89

The following carboxylic acids were prepared from the correspondingesters according to the general procedure of Example 26.

76. α-Hexyl-4-[(2-hydroxybenzoyl)amino]-1H-imidazole-1-acetic acid, 89%yield.

Analysis for C₁₈ H₂₃ N₃ O₄ :

Calc.: C, 62.59; H, 6.71; N, 12.17;

Found: C, 62.63; H, 6.60; N, 11.89.

77.α-Hexyl-4-{[(2-hydroxy-1-naphthalenyl)-carbonyl]amino}imidazole-1-aceticacid, 2.8% yield.

Analysis for C₂₂ H₂₅ N₃ O₄ :

Calc.: C, 66.82; H, 6.37; N, 10.63;

Found: C, 66.95; H, 6.13; N, 10.41.

78. α-Hexyl-4-[(3-hydroxybenzoyl)amino]-1H-imidazole-1-acetic acidhemihydrate, 77% yield.

Analysis for C₁₈ H₂₃ N₃ O₄.0.5 H₂ O:

Calc.: C, 60.93; H, 6.77; N, 11.85;

Found: C, 60.59; H, 6.60; N, 11.59.

79. α-Hexyl-4-[(3,4-dihydroxybenzoyl)amino]-1H-imidazole-1-acetic acid(1.75 hydrate), 50% yield.

Analysis for C₁₈ H₂₃ N₃ O₅.1.75 H₂ O:

Calc.: C, 55.01; H, 6.61; N, 10.68;

Found: C, 54.92; H, 6.19; N, 10.49.

80. α-Hexyl-4-[(3,5-dihydroxybenzoyl)amino]-1H-imidazole-1-acetic acid(0.75 hydrate), 62% yield.

Analysis for C₁₈ H₂₃ N₃ O₅.0.75 H₂ O:

Calc.: C, 67.75; H, 6.42; N, 11.23;

Found: C, 57.54; H, 6.49; N, 11.69.

81.α-Hexyl-4-({[(4-hydroxyphenyl)methyl]-amino}carbonyl)-1H-imidazole-1-aceticacid hydrochloride, 84% yield. MS:M⁺ =360.

82. α-Hexyl-4-{[(2-hydroxyphenyl)amino]-carbonyl}-1H-imidazole-1-aceticacid hydrochloride. MS:M⁺ =317.

83.α-Hexyl-4-({[2-(hydroxymethyl)phenyl]-amino}carbonyl)-1H-imidazole-1-aceticacid hydrochloride, 94% yield.

Analysis for C₁₉ H₂₅ N₃ O₄.HCl:

Calc.: C, 57.65; H, 6.62; N, 10.61;

Found: C, 57.51; H, 6.85; N, 10.43.

84.α-Hexyl-4-({[2-(4-hydroxybutyl)phenyl]-amino}carbonyl)-1H-imidazole-1-aceticacid hydrochloride, 82% yield.

Analysis for C₂₂ H₄₁ N₃ O₄.HCl:

Calc.: C, 60.33; H, 7.37; N, 9.59;

Found: C, 60.55; H, 7.43; N, 9.46.

85.α-Hexyl-4-({[3-(hydroxymethyl)phenyl]-amino}carbonyl)-1H-imidazole-1-aceticacid hydrochloride, 98% yield.

Analysis for C₁₉ H₂₅ N₃ O₄.HCl:

Calc.: C, 57.64; H, 6.62; N, 10.61;

Found: C, 57.85; H, 6.74; N, 10.36.

86.α-Hexyl-4-({[2-(2-hydroxyethyl)phenyl]-amino}carbonyl)-1H-imidazole-1-aceticacid hydrochloride, 98% yield.

Analysis for C₂₀ H₂₇ N₃ O₄.HCl:

Calc.: C, 58.60; H, 6.89; N, 10.25;

Found: C, 58.37; H, 7.04; N, 9.55.

87.α-Hexyl-4-({[4-(2-hydroxyethyl)phenyl]-amino}carbonyl)-1H-imidazole-1-aceticacid hydrochloride, 98% yield.

Analysis for C₂₀ H₂₇ N₃ O₄.HCl:

Calc.: C, 58.60; H, 6.89; N, 10.25;

Found: C, 58.62; H, 6.77; N, 10.53.

88. α-Butyl-4-{[(4-hydroxyphenyl)amino]-carbonyl}-1H-imidazole-1-aceticacid hydrochloride. MS:M⁺ =317.

89. α-Butyl-4-{[(2-hydroxyphenyl)amino]-carbonyl}-1H-imidazole-1-aceticacid hydrochloride. MS:M⁺ =317.

EXAMPLE 90 4-[(2-Ethoxycarbonylphenyl)methyl]-α-hexyl-benzeneacetic acidmethyl ester

A. Preparation of 2-benzylbenzoic acid ethyl ester.

To a solution of 10.05 g of α-phenyl-o-toluic acid in ethanol wasbubbled hydrogen chloride gas for 20 minutes. The mixture was thenheated at reflux for 6 hours and stirred overnight at room temperature.The solvent was removed by evacuation and the residue taken up indiethyl ether. The ether solution was washed with a dilute sodiumhydroxide solution, water, and a saturated sodium chloride solution,dried over magnesium sulfate, and concentrated in vacuo to provide 11 gof the desired subtitled intermediate. NMR.

B. Preparation of 2-(4-octanoylbenzyl)benzoic acid ethyl ester.

To a solution of 10.8 g of the ester from Example 90A above indichloromethane cooled to approximately 0° C. were added 15.1 g ofaluminum chloride. A solution of 7.7 g of octanoyl chloride in methylenechloride was added dropwise over a 45-minute period. The mixture wasallowed to warm to room temperature and stirred for 18 hours. Themixture was poured into a mixture of ice in concentrated hydrochloricacid. After stirring for one hour, the layers were separated and theorganic layer washed with a saturated sodium chloride solution, driedover magnesium sulfate, and concentrated in vacuo. The resulting oil waspurified by high pressure liquid chromatography eluting with a 0-30%ethyl acetate in hexane gradient. The appropriate fractions werecombined and evaporated to provide 9.5 g of the desired subtitledintermediate. NMR.

Analysis for C₂₄ H₃₀ O₃ :

Calc.: C, 78.65; H, 8.25;

Found: C, 78.76; H, 7.95.

C. Preparation of4-[(2-ethoxycarbonyl-phenyl)methyl]-α-hexylbenzeneacetic acid methylester.

Following the procedure of Example 55B, 3.67 g of the ester intermediatefrom Example 90B above, 5.1 g of iodine, and 5.5 ml oftrimethylorthoformate were allowed to react to provide 3.6 g of thedesired titled intermediate. NMR, MS.

EXAMPLE 91 2'-Ethoxycarbonyl-α-hexyl-4-biphenylacetonitrile

A. Preparation of 2-phenylbenzoic acid ethyl ester.

In the same way as provided in Example 90A, 30 g of 2-phenylbenzoic acidwere treated with hydrogen chloride gas in ethanol and worked up toprovide 34 g of the desired subtitled intermediate. NMR.

B. Preparation of 2-(4-heptanoylphenyl)benzoic acid ethyl ester.

Following the procedure of Example 90B, 29 g of the ester from Example91A above, 21 ml of heptanoyl chloride, 41.5 g of aluminum chloride, and750 ml of dichloromethane were allowed to react provided 6.5 g of thedesired subtitled intermediate. NMR, MS.

Analysis for C₂₂ H₂₆ O₃ :

Calc.: C, 78.08; H, 7.74;

Found: C, 78.25; H, 7.91

C. Preparation of 4-(2-ethoxycarbonylphenyl)-α-hexylbenzyl alcohol.

To 5.2 g of the ketone intermediate from Example 91B above in 75 ml ofethanol cooled to approximately 0° C. were added 0.6 g of sodiumborohydride. After stirring in the cold for 30 minutes, the reactionmixture was allowed to warm to room temperature and stirred under anitrogen blanket for 1.5 hours. The solvent was removed in vacuo and theresidue taken up in ethyl acetate. The organic layer was washed withdilute hydrochloric acid. The aqueous layer was back extracted withethyl acetate and the combined organic phases were washed with asaturated sodium chloride solution, dried over magnesium sulfate, andconcentrated in vacuo to provide 5.0 g of the desired subtitledintermediate. NMR. MS.

Analysis for C₂₂ H₂₈ O₃ :

Calc.: C, 77.61; H, 8.29;

Found: C, 77.80; H, 8.22.

D. Preparation of 4-(2-ethoxycarbonylphenyl)-α-hexylbenzyl bromide.

Four grams of the alcohol intermediate from Example 91C above weredissolved in 150 ml of methylene chloride and cooled by means of anexternal ice bath. Under a nitrogen atmosphere, a solution of 1.3 ml ofphosphorus tribromide in methylene chloride was added dropwise over aperiod of 35 minutes. Stirring was continued for one hour, the ice bathwas removed, and the solution was allowed to warm to room temperaturefor one hour. The solution was added to a mixture of ice andconcentrated hydrochloric acid and, after reaching room temperature, wasextracted with ethyl acetate. The organic layer was washed sequentiallywith water and a saturated sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo to provide 4.3 g of thedesired subtitled intermediate. NMR. MS.

Analysis for C₂₂ H₂₇ BrO₂

Calc.: C, 65.51; H, 6.75;

Found: C, 65.74; H, 6.64.

E. Preparation of 2'-ethoxycarbonyl-α-hexyl-4-biphenylacetonitrile.

A solution of 3.1 g of the bromo intermediate from Example 91D above and0.42 g of sodium cyanide in 30 ml of dimethylsulfoxide was heated to60°-75° C. for 13 hours. An additional 0.1 g of sodium cyanide was addedand heating continued an additional 2 hours. The solution was added to600 ml of water and 400 ml of ethyl acetate. After adding dry sodiumchloride, the layers were separated. The organic layer was washed withwater and a saturated sodium chloride solution, dried over magnesiumsulfate and concentrated in vacuo. High pressure liquid chromatographyeluting first with two liters of hexane followed by a 0-25% ethylacetate in hexane gradient and combination and evaporation of therelevant fractions provided 1.4 g of the desired subtitled intermediate.NMR. MS.

EXAMPLE 92α-Hexyl-4-{[(3-amino-2-ethoxycarbonylphenyl)carbonyl]amino}imidazole-1-aceticacid ethyl ester

A mixture of 5.1 g ofα-hexyl-4-{[(3-nitro-2-ethoxycarbonylphenyl)carbonyl]amino}imidazole-1-aceticacid ethyl ester and 2.1 g of 5% palladium-on-carbon were hydrogenatedin the presence of 150 ml of methanol until consumption of hydrogenceased. The catalyst was removed by filtration and the filtrateconcentrated in vacuo to provide 4.7 g of the desired subtitledintermediate. NMR.

EXAMPLE 93α-Hexyl-4-{[3-(acetylamino)-2-carboxybenzoyl]amino}-1H-imidazole-1-aceticacid ethyl ester

Following the procedure of Example 2, 1.54 g of4-nitro-α-hexyl-1H-imidazole-1-acetic acid ethyl ester were hydrogenatedto the corresponding amine and allowed to react with 1.12 g of3-acetamidophthalic anhydride in ethyl acetate. After stirring at roomtemperature, the solution was concentrated in vacuo and a small amountethyl acetate added. After sitting overnight, the resulting solid wascollected by filtration. Crystallization from hot ethylacetate/methanol/hexanes provided 0.54 g of the desired intermediate,m.p. 144°-145° C. NMR.

Analysis for C₂₃ H₃₀ N₄ O₆ :

Calc.: C, 50.25; H, 6.59; N, 12.22;

Found: C, 50.03; H, 6.55; N, 12.26.

EXAMPLES 94-97

The following carboxylic acid derivatives were prepared from thecorresponding esters according to the procedure of Example 26.

94. 4-[(2-Carboxyphenyl)methyl]-α-hexyl-benzeneacetic acid, 66% yield,m.p. 119°-121° C. NMR, MS.

Analysis for C₂₂ H₂₆ O₄ :

Calc.: C, 74.55; H, 7.39;

Found: C, 74.39; H, 7.53.

95. α-Hexyl-2'-carboxy-4-biphenylacetic acid.

96. α-Hexyl-4-[(3-amino-2-carboxybenzoyl)amino]-1H-imidazole-1-aceticacid, 95% yield.

Analysis for C₁₉ H₂₄ N₄ O₅ :

Calc.: C, 58.75; H, 6.23; N, 14.42;

Found: C, 58.54; H, 5.95; N, 14.16.

97.α-Hexyl-4-{[3-(acetylamino)-2-carboxybenzoyl]amino}-1H-imidazole-1-aceticacid hemihydrate, m.p. 100°-104° C., 16% yield.

Analysis for C₂₁ H₂₆ N₄ O₆.0.5 H₂ O:

Calc.: C, 57.40; H, 6.19; N, 12.75;

Found: C, 57.24; H, 5.93; N, 12.57.

The compounds of Formula I are potent effective antagonists ofangiotensin II. As such, they are useful for treatingangiotensin-induced hypertension in mammals and will also be useful forthe treatment of congestive heart failure. The ability for compounds ofFormula I to block angiotensin II receptor binding was determined usingthe adrenal glomerulosa assay. The ability to antagonizeangiotensin-induced vasoconstriction was evaluated in the rabbit aortatest system.

Adrenal Glomerulosa Test System

Binding of I¹²⁵ -angiotensin II to adrenal membranes was routinelycarried out in 96-well filtration plates. Adrenal membranes wereprepared from the capsular portion (glomerulosal layer attached) of ratadrenal glands by differential centrifugation. Briefly, capsules werehomogenized in a solution containing sucrose, 250 mM; MgCl₂, 1 mM; andtris, 5 mM at pH 7.5 and 4° C. using a polytron at setting 5 for 20seconds. The homogenate was stirred, gently, for 15 minutes at 4° C. andthen centrifuged 10 minutes, at 1000×g, 4° C. The supernatant wascentrifuged 30 minutes, at 30,000 ×g, 4° C. and the resulting pelletresuspended in 50 mM tris. Membrane preparations were stored in aliquotsat -70° C. until used. Binding of I¹²⁵ -angiotensin II to adrenalmembranes was performed at room temperature for 90 minutes in 96-wellplates containing a hydrophilic polyvinylidene fluoride membrane (0.45μm, millipore-GV multiscreen). Each 250 μl incubate contained thefollowing (final concentration): tris, 50 mM; NaCl, 120 mM; MgCl₂, 5 mM;dithiothrietol 1 mM; bovine serum albumin, 0.05%; I¹²⁵ -angiotensin II,0.1 nM; and adrenal membrane protein, 8-15 μg. Antagonists were added inconcentrations from 10 nM to 100 μM. Non-specific binding was measuredin the presence of 0.1 μM Sar₁, Ile₈ angiotensin II. Binding wasterminated by vacuum filtration. Receptor-ligand complex trapped onfilters was washed 3 times with 300 μl ice-cold wash solution (tris, 50mM; NaCl, 120 mM; MgCl₂, 5 mM; dithiothrietol, 1 mM). Filter discs weredried, punched out and counted in a gamma counter at 52% efficiency.Specific binding represented 96% of total binding (approximately 150fmol angiotensin II/mg protein). Data are expressed as the percentinhibition of I¹²⁵ angiotensin binding at 10⁻⁵ M of antagonist.

Rabbit Aorta Test System

New Zealand white rabbits (Hazelton, 2-3 kg) were sacrificed by cervicaldislocation and the thoracic aortas were removed and cleaned of excessfat and connective tissue. Rings of tissue (3 mm wide) were mounted in10 ml tissue baths between 2 L-shaped stainless steel hooks. The lowerhook was attached to a stationary rod and the upper hook to a forcedisplacement transducer (Grass model FT.03). The bath chambers weremaintained at 37° C., aerated with 95% O₂ /5% CO₂, and containedphysiological solution of the following composition (mM): NaCl, 117;glucose, 5.6; NaH₂ PO₄, 1.0; MgSO₄, 0.7; KCl, 5.2; CaCl₂, 1.8; NaHCO₃,26; and phentolamine HCl, 0.003.

Rings were equilibrated for 1 hour with 2 g of tension. During theequilibration period, the tissues were washed by overflow every 15minutes. Rings were then exposed to 10⁻⁸ M angiotensin II (AII) and wereallowed to contract until a steady state was reached. Tissues were thenwashed every 15 minutes for 1 hour. This was repeated every hour untilthe AII response stabilized. A cumulative concentration-response curveto AII (10⁻¹⁰ to 10⁻⁷ M) was then obtained. At the conclusion of theconcentration-response curve, tissues were washed every 2 minutes untilbaseline tension was reached, then every 15 minutes for 30 minutes.Compounds were added in a volume of 10 μl DMSO and allowed to incubatefor 30 minutes before repeating the concentration-response curve to AII.Contractions to AII were expressed as a percent of the maximumcontraction obtained in the control curve (the first AIIconcentration-response curve). EC₅₀ 's (concentration that contractedthe tissues to 1/2 the control maximum) for each curve were calculatedusing a 4 parameter logistics model (NonLin, SAS institute). Potencydata for each compound tested are expressed in Table 1 as the pA₂(defined as -log K_(B), where K_(B) =[molar concentration ofantagonist]/[(EC₅₀ AII with antagonist/EC₅₀ AII without antagonist)-1]).

                  TABLE 1                                                         ______________________________________                                                   Adrenal Glomerulosa                                                           (% Inhibition of                                                                             Rabbit Aorta                                        Example    Binding        (pA.sub.2)                                          ______________________________________                                         5         39             5.48                                                 9         25             4.74                                                10         57             5.63                                                12         44             5.60                                                14          2             4.26                                                15          5             4.12                                                18          3             3.10                                                26         57             4.99                                                27         64             6.85                                                28         10             5.46                                                29         40             4.59                                                30         66             6.96                                                31         70             5.51                                                32         54             4.67                                                33         42             6.20                                                34         31             5.72                                                35         36             5.58                                                36          5             4.93                                                37          0             5.80                                                38         30             5.78                                                39         44             6.18                                                40          9             5.79                                                41         30             6.19                                                42         58             6.48                                                43          0             6.02                                                44         67             5.40                                                45          0             5.38                                                46         39             4.36                                                47         39             5.30                                                48         61             4.92                                                49          9             4.39                                                50         42             6.07                                                51         80             5.57                                                52         44             5.08                                                53         42             5.22                                                54         40             4.86                                                55         13             5.90                                                56         75             5.98                                                57         77             5.58                                                58         69             5.37                                                59         67             5.51                                                60         15             5.08                                                76         35             5.90                                                77         36             5.26                                                78         21             5.10                                                79         18             4.96                                                81         41                                                                 82         62                                                                 83         53             5.41                                                84         77             5.64                                                85          0             4.80                                                86         57             5.49                                                87          7             4.63                                                88         22                                                                 89         54             4.41                                                94         58             5.78                                                96         59             6.43                                                97                        6.62                                                ______________________________________                                    

The term "pharmaceutically effective amount", as used herein, representsan amount of a compound of the invention which is capable of blockingangiotensin II receptors in mammals. The particular dose of compoundadministered according to this invention will, of course, be determinedby the particular circumstances surrounding the case, including thecompound administered, the route of administration, the particularcondition being treated, and similar considerations. The compounds canbe administered by a variety of routes including the oral, rectal,transdermal, subcutaneous, intravenous, intramuscular or intranasalroutes. A typical daily dose will contain from about 0.01 mg/kg to about20 mg/kg of the active compound of this invention. Preferred daily doseswill be about 0.05 to about 10 mg/kg, ideally about 0.1 to about 5mg/kg.

The compounds of Formula I are preferably formulated prior toadministration. Therefore, yet another embodiment of the presentinvention is a pharmaceutical formulation comprising a compound ofFormula I and one or more pharmaceutically acceptable carriers, diluentsor excipients therefor.

The present pharmaceutical formulations are prepared by known proceduresusing well known and readily available ingredients. In making thecompositions of the present invention, the active ingredient willusually be mixed with a carrier, or diluted by a carrier, or enclosedwithin a carrier which may be in the form of a capsule, sachet, paper orother container. When the carrier serves as a diluent, it may be asolid, semisolid or liquid material which acts as a vehicle, excipientor medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions and sterile packagedpowders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyland propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 5 to about 500 mg, more usually about 25 toabout 300 mg, of the active ingredient. The term "unit dosage form"refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalcarrier.

The following formulation examples are illustrative only and are notintended to limit the scope of the invention in any way.

FORMULATION 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                             Quantity                                                                      (mg/capsule)                                             ______________________________________                                        α-Hexyl-4-[3-hydroxy-2-(tetrazol-5-                                                            250                                                    yl)benzoyl]amino-1H-imidazole-                                                1-acetic acid                                                                 starch, dried          200                                                    magnesium stearate     10                                                     Total                  460     mg                                             ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

FORMULATION 2

A tablet is prepared using the ingredients below:

    ______________________________________                                                               Quantity                                                                      (mg/tablet)                                            ______________________________________                                        α-Hexyl-4-[3-hydroxymethyl-2-(tetrazol-                                                          250                                                  5-yl)benzoyl]amino-1H-imidazole-                                              1-acetic acid                                                                 cellulose, microcrystalline                                                                            400                                                  silicon dioxide, fumed   10                                                   stearic acid             5                                                    Total                    665    mg                                            ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg.

FORMULATION 3

An aerosol solution is prepared containing the following components:

    ______________________________________                                                             Weight %                                                 ______________________________________                                        α-Hexyl-4-[3-hydroxy-2-(tetrazol-5-                                                             0.25                                                  ylmethyl)benzoyl]amino-1H-imidazole-                                          1-acetic acid                                                                 ethanol                29.75                                                  Propellant 22          70.00                                                  (chlorodifluoromethane)                                                       Total                  100.00                                                 ______________________________________                                    

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to -30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propelant. The valveunits are then fitted to the container.

FORMULATION 4

Tablets each containing 60 mg of active ingredient are made as follows:

    ______________________________________                                        Hexyl-4-[3-hydroxy-2-(tetrazol-5-                                                                       60 mg                                               yl)]-1H-imidazole-1-acetic acid                                               starch                    45 mg                                               microcrystalline cellulose                                                                              35 mg                                               polyvinylpyrrolidone      4 mg                                                (as 10% solution in water)                                                    sodium carboxymethyl starch                                                                             4.5 mg                                              magnesium stearate        0.5 mg                                              talc                      1 mg                                                Total                     150 mg                                              ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

FORMULATION 5

Capsules each containing 80 mg of medicament are made as follows:

    ______________________________________                                        Hexyl-4-[(3-methylsulfonylamino-2-                                                                   80 mg                                                  (tetrazol-5-yl)benzoyl]amino-1H-                                              imidazole-1-acetic acid                                                       starch                 59 mg                                                  microcrystalline cellulose                                                                           59 mg                                                  magnesium stearate      2 mg                                                  Total                  200 mg                                                 ______________________________________                                    

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

FORMULATION 6

Suppositories each containing 225 mg of active ingredient may be made asfollows:

    ______________________________________                                        β-Hexyl-4-[3-hydroxy-2-(tetrazol-5-                                                              225 mg                                                yl)benzoyl]amino-1H-imidazole-                                                1-propionic acid                                                              saturated fatty acid glycerides                                                                     2,000 mg                                                Total                 2,225 mg                                                ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

FORMULATION 7

Suspensions each containing 50 mg of medicament per 5 ml dose are madeas follows:

    ______________________________________                                        α-Hexyl-4-[3-hydroxy-2-(tetrazol-5-                                                             50     mg                                             yl)benzoyl]phenylacetic acid                                                  sodium carboxymethyl cellulose                                                                        50     mg                                             syrup                   1.25   ml                                             benzoic acid solution   0.10   ml                                             flavor                         q.v.                                           color                          q.v.                                           purified water to total 5      ml                                             ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

FORMULATION 8

An intravenous formulation may be prepared as follows:

    ______________________________________                                        α-Hexyl-4-[2-carboxy-3-hydroxybenzoyl)-                                                           250    mg                                           amino]-1H-imidazole-1-acetic acid                                             monohydrate                                                                   isotonic saline           1000   ml                                           ______________________________________                                    

The solution of the above ingredients is administered intravenously at arate of 1 ml per minute to a subject in need of treatment.

We claim:
 1. A compound of the formula ##STR11## or pharmaceuticallyacceptable salt or solvate thereof ##STR12## A₂ is N: A₁ and A₃ are eachCH;X is --CO--, --COHN--, --NHCO--, --CH₂ CONH--, --O--, --NH--, --CH₂-- or a bond; each R₁ is independently --(CH₂)_(n) R₃ ; R₂ is C₄ -C₇straight chain alkyl; each R₃ is independently --COOH or 5-tetrazolyl;each n is independently 0, 1, 2, 3, or 4; R₄ is H, OH, halo, nitro,methyl, amino, acetamido, or methanesulfonamido; Q is a bond or --O--;and W is H, methyl, ethyl, or hydroxy.
 2. A compound of claim 1 of theFormula ##STR13## or a pharmaceutically acceptable salt or solvatethereof wherein R₄ ' is hydrogen or hydroxy.
 3. The compound of claim 2which isα-hexyl-4-[(2-carboxy-3-hydroxybenzoyl)amino]-1H-imidazole-1-acetic acidor a pharmaceutically acceptable salt or solvate thereof.
 4. Thecompound of claim 2 which isβ-hexyl-4-[(2-carboxy-3-hydroxybenzoyl)amino]-1H-imidazole-1-propanoicacid or a pharmaceutically acceptable salt or solvate thereof.
 5. Thecompound of claim 2 which isα-hexyl-4-{[2-(tetrazol-5-yl)benzoyl]amino}-1H-imidazole-1-acetic acidor a pharmaceutically acceptable salt or solvate thereof.
 6. A method ofblocking angiotensin II receptors in mammals which comprisesadministering to a mammal requiring inhibition of the action ofangiotensin II at its receptors a pharmaceutical amount of a compound ofclaim
 1. 7. A method of blocking angiotensin II receptors in mammalswhich comprises administering to a mammal requiring inhibition of theaction of angiotensin II at its receptors a pharmaceutical amount of acompound of claim
 2. 8. The method of claim 7 employingα-hexyl-4-[(2-carboxy-3-hydroxybenzoyl)amino]-1H-imidazole-1-acetic acidor a pharmaceutically acceptable salt or solvate thereof.
 9. The methodof claim 7 employingβhexyl-4-[(2-carboxy-3-hydroxybenzoyl)amino]-1H-imidazole-1-propanoicacid or a pharmaceutically acceptable salt or solvate thereof.
 10. Themethod of claim 7 employingα-hexyl-4-{[2-(tetrazol-5-yl)benzoyl]amino}-1H-imidazole-1-acetic acidor a pharmaceutically acceptable salt or solvate thereof.
 11. A methodof treating hypertension in a mammal comprising administering to amammal in need of treatment from hypertension an antihypertensive amountof a compound of claim
 1. 12. A method of treating hypertension in amammal comprising administering to a mammal in need of treatment fromhypertension an antihypertensive amount of a compound of claim
 2. 13.The method of claim 12 employingα-hexyl-4-[(2-carboxy-3-hydroxybenzoyl)amino]-1H-imidazole-1-acetic acidor a pharmaceutically acceptable salt or solvate thereof.
 14. The methodof claim 12 employingβ-hexyl-4-[(2-carboxy-3-hydroxybenzoyl)amino]-1H-imidazole-1-propanoicacid or a pharmaceutically acceptable salt or solvate thereof.
 15. Themethod of claim 12 employingα-hexyl-4-{[2-(tetrazol-5-yl)benzoyl]amino}-1H-imidazole-1-acetic acidor a pharmaceutically acceptable salt or solvate thereof.
 16. Apharmaceutical formulation comprising a compound of claim 1 and one ormore pharmaceutically acceptable carriers, diluents, or excipientstherefor.
 17. A pharmaceutical formulation comprising a compound ofclaim 2 and one or more pharmaceutically acceptable carriers, diluents,or excipients therefor.
 18. A formulation of claim 17 employingα-hexyl-4-](2-carboxy-3-hydroxybenzoyl)amino]-1H-imidazole-1-acetic acidor a pharmaceutically acceptable salt or solvate thereof.
 19. Aformulation of claim 17 employingβ-hexyl-4-[(2-carboxy-3-hydroxybenzoyl)amino]-1H-imidazole-1-propanoicacid or a pharmaceutically acceptable salt or solvate thereof.
 20. Aformulation of claim 17 employingα-hexyl-4-{[2-(tetrazol-5-yl)benzoyl]amino}-1H-imidazole-1-acetic acidor a pharmaceutically acceptable salt or solvate thereof.